Effect of nitric oxide synthesis inhibition on mouse liver and brain metallothionein expression

The role of nitric oxide (NO) production on metallothionein (MT) regulation in the liver and the brain has been studied in mice by means of the admini stration of nitric oxide synthase (NOS) inhibitors. Mice injected with eith er the arginine analog N-G-monomethyl-1-arginine (L-NMMA) or the heme bindi ng compound 7-nitro indazole (7-NI) showed consistently increased liver MT- I mRNA and MT-I+II total protein levels, suggesting that NO is involved in the hepatic MT regulation. In agreement with the liver results, in situ hyb ridization analysis demonstrated a significant upregulation of the brain MT -I isoform in areas such as the cerebrum cortex, neuronal CA1-CA3 layers an d dentate gyrus of the hippocampus, and Purkinje cell layer of the cerebell um, in 7-NI treated mice. The same trend was observed for the brain specifi c isoform, MT-III, but to a much lower extent. The effect of NOS inhibition was also evaluated in a MT-inducing condition, namely during immobilizatio n stress. In both the liver and the brain, stress upregulated the MT-I isof orm, and 7-NI significantly reduced or even blunted the MT-I response to st ress, suggesting a mediating role of NO on MT-I regulation during stress. S tress also increased the MT-III mRNA levels in some brain areas, an effect blunted by the concomitant administration of 7-NI, which in some areas even decreased MT-III mRNA levels below the saline injected mice. Results in pr imary culture of neurons and astrocytes demonstrate significant effects of the NOS inhibitors in some experimental conditions. The present results sug gest that NO may have some role on MT regulation in both the liver and the brain. (C) 1999 Elsevier Science Ltd. All rights reserved.